Diabetes, also referred to as diabetes mellitus, is a syndrome characterized by hyperglycemia resulting from absolute or relative impairment in insulin secretion and/or insulin action (The Merck Manual of Diagnosis and Therapy, 17th Ed, Section 2, Chapter 13; Berkow, R., Beers, M. H., and Burs, M., Eds.; John Wiley & Sons, 1999). It is characterized as a progressive breakdown in normal insulin-related usage of glucose. In order to function properly, the body's use of glucose must comprise a balanced output of insulin from the pancreas to transport glucose effectively to other organs and tissues for storage. Any insulin imbalance or loss of sensitivity can cause a chronic overabundance of glucose leading to diabetes.
In 2006, according to the World Health Organization, at least 171 million people worldwide suffer from diabetes. Its incidence is increasing rapidly, and it is estimated that by the year 2030, this number will double. Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries.
For at least 20 years, diabetes rates in North America have been increasing substantially. According to the American Diabetes Association, it is estimated that a total of 20.8 million people in the United States, about 7.0% of the population, have diabetes in one form or another, and of these people, about 6.2 million people undiagnosed. (http://www.diabetes.org/diabetes-statistics/prevalence.jsp). Additionally, about 54 million people are predicted to be presently prediabetic.
Fasting Plasma Glucose Test (FPG) or an Oral Glucose Tolerance Test (OGTT) are used to diagnose pre-diabetes or diabetes. With the FPG test, a fasting blood glucose level between 100 and 125 mg/dl signals pre-diabetes. A fasting blood glucose level of 126 mg/dl or higher indicates diabetes. In the OGTT test, a person's blood glucose level is measured after a fast and two hours after drinking a glucose-rich beverage. If the two-hour blood glucose level is between 140 and 199 mg/dl, the person tested has pre-diabetes. If the two-hour blood glucose level is at 200 mg/dl or higher, the person tested has diabetes.
There are several types of diabetes. In type 1 diabetes, (also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes or autoimmune diabetes) patients produce little or no insulin, the hormone which regulates glucose utilization, because the immune system attacks the cells in the pancreas that make and release insulin. As these cells die, blood sugar levels rise. Generally, type I diabetes is characterized clinically by hyperglycemia and a propensity to develop diabetic ketoacidosis (DKA), wherein the pancreas produces little or no insulin. Thus, people with type 1 diabetes need insulin shots. Type 1 diabetes, which accounts for 5% to 10% of all diagnosed cases of diabetes, typically affects children, although adults can develop it. Autoimmune, genetic, and environmental factors are involved in the development of this type of diabetes.
Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, usually develops later in life. Insulin is still produced in the body, however the organs and tissues lose their ability to respond effectively to insulin. Although type 2 diabetes is also characterized by hyperglycemia and insulin resistance, it is often associated with visceral/abdominal obesity, has very little or no propensity to ketoacidosis. It is typically diagnosed in patients older than 30, and has significant but variable levels of insulin secretion relative to plasma glucose levels. The CDC estimates type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes. Risk factors for type 2 diabetes include older age, obesity, family history of diabetes, prior history of gestational diabetes, impaired glucose tolerance, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Pacific Islanders are at particularly high risk for type 2 diabetes.
Gestational diabetes is a third type of diabetes that develops in about 4% percent of all pregnancies—about 135,000 cases in the United States each year—and usually ends with the pregnancy. A small percentage of diabetes may also result from specific genetic syndromes, surgery, drugs, malnutrition, infections, and other illnesses.
Additionally, millions of people have a condition called pre-diabetes. They have higher-than-normal blood sugar levels, but not high enough to be clinically defined as diabetics. These people are at extremely high risk for developing type 2 diabetes. It has been suggested that both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are intermediate states in the transition from normal glucose tolerance (NGT) to type 2 diabetes and have been termed as “pre-diabetes”. They are associated with a high risk for progression to type 2 diabetes. Hepatic glucose production (HGP) is the principal determinant of fasting plasma glucose (FPG). It has been demonstrated that, in the non-diabetic range, the rise in fasting plasma glucose (FPG) concentration is associated with a mild decrease in hepatic glucose production (HGP) and a marked decrease in the glucose clearance rate. During the fasting state, the decrease in glucose clearance results in an increase in FPG concentration which stimulates basal insulin secretion. The rise in fasting plasma insulin concentration, in turn, inhibits HGP, thus attenuating the rise in FPG. The high fasting blood glucose in these subjects can thus be explained by the decrease in glucose clearance. (Rucha Jani, abstract of American Association of Clinical Endocrinologists Sixteenth Annual Meeting and Clinical Congress, Apr. 11-16, 2007, Washington State Convention & Trade Center in Seattle).
The chronic overabundance of glucose associated with diabetes damages the body's blood vessels and can lead to many related disorders. Generally, high glucose levels in the blood plasma (hyperglycemia) can lead higher than normal amounts of particular hemoglobin, HbA1c. Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease. Patients with type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications. In extreme cases, diabetes can result in the amputation of limbs and death.
Diabetes is also the leading cause of kidney failure in the U.S. (see American Kidney Fund, 2007; Middleton, et al. (2006) The unrecognized prevalence of chronic kidney disease in diabetes. Nephrology Dialysis Transplantation 21 (1):88-92). In fact, almost 45% of all kidney failure cases are caused by diabetes. Drugs and diet can help manage diabetes and prevent complications, but some people may still develop kidney disease, even with good medical care.
Other conditions related to diabetes reported by the CDC include: nervous system diseases, which often includes impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and other nerve problems, periodontal disease, which is a type of gum disease that can lead to tooth loss, complications of pregnancy, including congenital malformations and death of the fetus, and other complications such as diabetic ketoacidosis and hyperosmolar nonketotic coma. Many patients who have insulin resistance or type 2 diabetes also often have several symptoms that together are referred to as syndrome X, or the metabolic syndrome.
Current Therapies for Diabetes
Therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension have been considered critically important in the clinical management and treatment of diabetes mellitus. Lack of insulin production by the pancreas makes type 1 diabetes particularly difficult to control. Treatment generally requires a strict lifestyle regimen including multiple daily insulin injections.
Current drugs used for managing type 2 diabetes, generally fall within five classes of compounds: the biguanides, thiazolidinediones, the sulfonylureas, benzoic acid derivatives and alpha-glucosidase inhibitors. The biguanides, such as metformin, are believed to prevent excessive hepatic gluconeogenesis. The thiazolidinediones are believed to act by increasing the rate of peripheral glucose disposal. The sulfonylureas, such as tolbutamide and glyburide, the benzoic acid derivatives, such as repaglinide, and the alpha-glucosidase inhibitors, such as acarbose, lower plasma glucose primarily by stimulating insulin secretion.
A widely used drug treatment involves the administration of meglitinide or a sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues. These drugs increase the plasma level of insulin by stimulating the pancreatic β-cells to secrete more insulin. Dangerously low levels of plasma glucose can result from administration of insulin and/or insulin secretagogues, and an increased level of insulin resistance can occur.
The biguanides are another class of drugs that are widely used to treat type 2 diabetes. The two best known biguanides, phenformin and metformin, cause some correction of hyperglycemia without risk of causing hypoglycemia. However, phenformin and metformin can induce lactic acidosis and nausea/diarrhea.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) can ameliorate hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of elevated plasma glucose levels without the occurrence of hypoglycemia. The glitazones that are currently marketed (rosiglitazone and pioglitazone) are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones.
Probucol Derivatives
Derivatives of probucol have been developed as therapeutics, for example, for the treatment of cardiovascular disease and as anti-inflammatory agents. Probucol contains two hydroxyl groups and can be modified to form mono-substituted or di-substituted derivatives. Mono-esters and ethers of probucol have been reported to be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and dermatitis. Methods for treating transplant rejection using mono-substituted derivatives of probucol also have been reported. See U.S. Pat. Nos. 6,670,398 and 7,087,645.
U.S. Pat. No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. A series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: FR 2168137 (bis 4hydroxyphenylthioalkane esters); FR 2140771 (tetralinyl phenoxy alkanoic esters of probucol); FR 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); FR 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4 nicotinoyloxyphenylthio)-propanes; and FR 2130975 (bis(4-phenoxyalkanoyloxy)phenylthio)alkanes).
European Patent No. 0348203 to Shiongi Seiyaku Kabushiki Kaisha discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. Hydroxamic acid derivatives of these compounds are disclosed in European Patent No. 0405788 to Shiongi Seiyaku Kabushiki Kaisha and are alleged as useful for the treatment of arteriosclerosis, ulcer, inflammation and allergies. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Pat. No. 4,954,514 to Kita, et al.
WO 98/51662 (also U.S. Pat. No. 6,121,319) and WO 98/51289 (also U.S. Pat. No. 6,147,250) to AtheroGenics, Inc. describe certain probucol derivatives and their use for the treatment of disorders mediated including inflammatory and cardiovascular disorders.
WO 01/70757 (also U.S. Pat. No. 6,852,878) to AtheroGenics, Inc. also describes the use of certain thioethers of the following formula, and pharmaceutically acceptable salts thereof:
whereinRa, Rb, Rc, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C1-10 alkyl or substituted C1-10 alkyl, terminated by sulfonic acid, (iv) C1-10 alkyl or substituted C1-10 alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C1-10 alkyl-O—C(O)—C1-10 alkyl, (vi) straight chained polyhydroxylated C3-10 alkyl; (vii) —(CR2)1-6—COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) —(CR2)1-6—X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
Meng et al., discloses a series of phenolic inhibitors of TNF-inducible expression of VCAM-1 with concurrent antioxidant and lipid-modulating properties. The compounds disclosed have demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia. (Novel Phenolic Antioxidants as Multifunctional Inhibitors of Inducible VCAM-1 Expression for Use in Atherosclerosis, Bioorganic & Med. Chem Ltrs. 12 (18), 2545-2548, 2002).
WO2006/007508 to AtheroGenics, Inc. (also U.S. Patent Publication No. 20060058268) describes methods for treating certain microvascular diseases related to diabetes, including neuropathy, nephropathy, or retinopathy in a mammal, the method comprising administering to the mammal an effective amount of certain probucol derivatives
Given the high and increasing incidence of diabetes worldwide, there is a need to provide new therapies for its treatment.
Therefore, it is an object of the present invention to provide pharmaceutical compositions and methods for treatment or prophylaxis of diabetes and related disorders.